Project Summary A research plan is proposed to engineer goats that produce fully human immunoglobulin. These animals will be evaluated as a candidate platform system for production of both targeted therapeutic immunoglobulin as well as reagent antibodies for standards and controls of serological assays of human clinical samples. Previous studies have demonstrated that ungulates such as cattle can produce large amounts of human immunoglobulins and show extremely high titers and neutralizing antibody activities against various antigens, including infectious diseases, toxins and other targets following multiple immunizations. In this study, SAB Capra LLC (SAB) and Utah State University intend to expand and optimize this technology by producing transchromosomic (Tc) goats containing a human artificial chromosome vector (HAC) which contains the entire germline repertoire of the human antibody genes. In addition, the participants will produce goat fibroblast cell lines where the endogenous goat antibody genes will be silenced using current gene editing technologies. There are three specific aims in this project: (1) develop the first human immunoglobulin producing Tc goats by transferring the HAC containing the germ line human antibody heavy and light chain genes to KO fetal fibroblast cell lines; (2) evaluate and characterize human immunoglobulin produced in the Tc goats from Aim 1 and determine the stability and antibody production of the Tc goats and compare the immunoglobulin response to Tc cattle as well as humans; (3) produce high titer targeted immunoglobulin to pandemic flu strains (H7N9 and/or H5N1) for target specific evaluation. Data generated from this study will enable further work to be conducted to determine the usefulness of small ungulates producing human antibodies used as production animals to produce targeted human immunoglobulin therapeutic candidates and diagnostic standards and controls to emerging diseases. If this project is completed successfully, it will also have a broad implication that SAB?s platform technology can be used in both a large (cattle) and small (goat) ungulate species providing greater flexibility in producing product candidates. The addition of a small ungulate species will reduce costs associated with generating antibodies for small volume products as well as targeted human immunoglobulins used as diagnostic standards and controls for testing human clinical samples.